Expression of thrombomodulin in atherosclerotic lesions and mitogenic activity of recombinant thrombomodulin in vascular smooth muscle cells

Citation
G. Tohda et al., Expression of thrombomodulin in atherosclerotic lesions and mitogenic activity of recombinant thrombomodulin in vascular smooth muscle cells, ART THROM V, 18(12), 1998, pp. 1861-1869
Citations number
45
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
ISSN journal
1079-5642 → ACNP
Volume
18
Issue
12
Year of publication
1998
Pages
1861 - 1869
Database
ISI
SICI code
1079-5642(199812)18:12<1861:EOTIAL>2.0.ZU;2-5
Abstract
Thrombomodulin (TM), a thrombin receptor protein found on the endothelial c ell surface, contains 6 tandem epidermal growth factor (EGF)-like structure s. Recombinant human TM peptide containing these 6 EGF-like domains (rTME1- 6) exhibits mitogenic activity in Swiss 3T3 cells. We examined the localiza tion of TM in atherosclerotic lesions and the effects of rTME1-6 on the gro wth of cultured rat vascular smooth muscle cells (SMCs). Immunohistochemica l analysis demonstrated that TM antigen was localized on monocytes, macroph ages, and vascular SMCs. In cultured vascular SMCs, rTME1-6 accelerated [H- 3]thymidine uptake into DNA in a dose-dependent manner up to 3.4 times the control level. This mitogenic activity was abolished by addition of polyclo nal anti-human TM antibody. The rTME1-6-induced mitogenesis was enhanced by EGF. However, a neutralizing monoclonal antibody against the EGF receptor (monoclonal antibody 225) did not inhibit the mitogenic activity of rTME1-6 . Calphostin C, a specific protein kinase C inhibitor, and lavendustin-A, a n inhibitor of EGF receptor-specific protein tyrosine kinase-inhibited the. mitogenic activities of both rTME1-6 and EGF. Finally, rTME1-6 treatment i ncreased the level of phosphorylated mitogen-activated protein kinase in SM Cs. Together, these results suggest that TM expression in atherosclerotic l esions may be associated with promotion of atherosclerosis through its mito genic activity in vascular SMCs.